Mechanisms and Treatment of Network Dysfunction in Alzheimer's Disease

阿尔茨海默病网络功能障碍的机制和治疗

基本信息

批准号：
8892948
负责人：
Keith Alan Vossel
金额：
$ 15.28万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8892948
关键词：
Acute Affect Age Aging Alzheimer&apos s Disease American Americas Amyloid Amyloid beta-Protein Precursor Antiepileptic Agents Axonal Transport Behavioral Biological Neural Networks Biomedical Engineering Brain Caregivers Cell Culture Techniques Clinical Clinical Research Clinical Trials Cognitive Cognitive deficits Defect Dementia Deposition Development Development Plans Disease Electroencephalography Epilepsy Eye FDA approved Feeling Feeling hopeless Frequencies Frontotemporal Dementia Functional disorder Future Genetic Goals Healthcare Systems Hippocampus (Brain)Histology Human Image Impaired cognition Impairment Incidence Investigation KCNA1 channel Laboratories Lewy Body Dementia Magnetoencephalography Memory Mentors Microfluidics Microscopy Mind Mitochondria Monitor Morbidity - disease rate Mus Nerve Degeneration Nerve Growth Factor Receptors Neurodegenerative Disorders Neurology Neurons Neurosciences Participant Pathogenesis Pathology Pathway interactions Patient Care Patients Pharmaceutical Preparations Physicians Population Prevalence Research Research Proposals Scientist Seizures Source Staging Subclinical Seizures Synapses Systems Development Testing Therapeutic Therapeutic Trials Time Training Transgenic Mice Voltage-Gated Potassium Channel age related amyloid peptide base behavioral neurology career career development clinical investigation design experience follow-up in vivo mild cognitive impairment mortality mouse model network dysfunction neurodegenerative dementia neuronal excitability neurotoxic novel novel therapeutic intervention peptide A prevent protein expression small hairpin RNA tau Proteins tau expression translational clinical trial two-photon

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and other age-related neurodegenerative disorders are a major source of morbidity and mortality. In the U.S. alone, some 5 million people have AD, a relentless and fatal condition that devastates the mind and engenders feelings of hopelessness in caregivers. The urgency in finding a cure for AD has never been stronger. AD is associated with an increased incidence of seizures as well as cognitive decline. Seizures and subclinical excitatory neuronal activity may contribute to cognitive deficits. We propose to investigate neuroprotective strategies to counter neuronal overexcitation and seizures in AD and identify a population who could benefit from such therapies. The laboratory investigation focuses on the axonal transport of two cellular components that tightly regulate neuronal activity-mitochondria and the voltage-gated potassium channel Kv1.1. The neurotoxic peptide amyloid-� (A�) impairs axonal transport of mitochondria, and reduction of the microtubule-associated protein tau completely abolishes this effect. Tau reduction also protects against seizures and behavioral deficits in transgenic mouse models of AD. These findings suggest a pathogenic mechanism for A� and tau involving axonal transport and neuronal excitability. In Aim 1, we will investigate mechanisms by which tau and A� regulate the axonal transport of mitochondria and Kv1.1, and study the effects of tau reduction on axonal transport of these cargoes in vivo in a mouse model of AD. Aim 2 is a translational clinical investigation of the extent of subclinical epileptiform activity in people with mild cognitive impairment and AD with an eye toward future therapeutic trials using antiepileptic medications or tau-targeted strategies. The candidate is a physician-scientist with a strong commitment to a career in academic neurology focused on identifying novel therapies for AD and related dementias. The candidate has an MSc in biomedical engineering and an MD with clinical training in neurology and subspecialty training in behavioral neurology and neurodegenerative dementias. The research proposal and career development plan build upon his training in neuroscience, aging, and neurodegenerative diseases to provide expertise in transgenic mouse models of AD, histology, cell culture, microfluidics chambers, time-lapse microscopy, transcranial two-photon imaging, and translational clinical trials. Dr. Lennart Mucke, a physician-scientist who cares for patients with dementia and specializes in transgenic mouse models of neurodegenerative disease, is the candidate's sponsor. The mentoring and research experience described in this proposal will facilitate the candidate's goal of developing a strong independent research career.

描述（由申请人提供）：阿尔茨海默病 (AD) 和其他与年龄相关的神经退行性疾病是发病率和死亡率的主要来源。仅在美国，就有约 500 万人患有 AD，这是一种严重破坏精神和健康的致命疾病。寻找 AD 治疗方法的紧迫性与癫痫发作以及认知能力下降有关。兴奋性神经活动可能导致认知缺陷。我们建议研究神经保护策略，以对抗 AD 中的神经元过度兴奋和癫痫发作，并确定可以从此类疗法中受益的人群。实验室研究的重点是严格调节神经元的两种细胞成分的轴突运输。活性线粒体和电压门控钾通道 Kv1.1 神经毒性肽淀粉样蛋白 -� (A�) 损害线粒体的轴突运输，并减少微管相关蛋白。 tau 蛋白的减少还可以防止 AD 转基因小鼠模型中的癫痫发作和行为缺陷。在目标 1 中，我们将研究 A� 和 tau 蛋白轴突运输和神经兴奋性的致病机制。 tau 和 A� 调节线粒体和 Kv1.1 的轴突运输，并在 Aim 小鼠模型中研究 tau 减少对这些货物体内轴突运输的影响。 2 是一项针对轻度认知障碍和 AD 患者亚临床癫痫样活动程度的转化临床研究，着眼于未来使用抗癫痫药物或 tau 靶向策略的治疗试验。该候选人拥有生物医学工程硕士学位和接受过神经病学临床培训以及行为神经病学和神经退行性疾病亚专业培训的医学博士。研究计划和职业发展计划建立在他在神经科学、衰老和神经退行性疾病方面的培训基础上，提供 AD 转基因小鼠模型、组织学、细胞培养、微流体室、延时显微镜、经颅双光子成像、 Lennart Mucke 博士是一位护理痴呆症患者并专门研究神经退行性疾病转基因小鼠模型的医师科学家，他是该候选人的发起人。本提案中描述的指导和研究经验将有助于候选人实现发展强大的独立研究职业的目标。